Theoretical and Experimental Study of the Water-Based Drug Delivery under the Nail Plate by Er-Laser Radiation

Andrey V. Belikov
ITMO University, Saint Petersburg, Russia

Anastasia D. Kozlova (Login required)
ITMO University, Saint Petersburg, Russia

Sergey N. Smirnov
ITMO University, Saint Petersburg, Russia

Paper #3471 received 05 Dec 2021; revised manuscript received 07 Mar 2022; accepted for publication 08 Mar 2022; published online 31 Mar 2022.

DOI: 10.18287/JBPE22.08.010305


Double-stage active laser drug delivery (DSLADD) of an aqueous solution of methylene blue using Er:YLF laser radiation experimentally was investigated. Model for describe of the delivery of local drugs under a microporated nail plate taking into account the peculiarities of laser radiation exposure, capillary effects in microholes and diffusion in the nail plate was developed. The phenomenon of spreading of the drug consisting in the fact that after laser action drug is distributed in the nail bed not only in the area of the nail bed located directly under the microhole, but also along the border of the nail plate and the nail bed around the microhole was observed for the first time. Calculations performed within the framework of the developed model showed that, taking into account spreading phenomenon, the density of filling the nail area with microholes can be significantly reduced, which can proportionally increase the productivity of laser delivery in general.


dual-stage method for active laser drug delivery; drug delivery model; laser microporation; nail; nail permeability coefficient

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1. C. C. Lai, C.-K.Tan. Y.-T. Huang, P.-L. Shao, and P.-R. Hsueh, “Current challenges in the management of invasive fungal infections,” Journal of Infection and Chemotherapy 14(2), 77–85 (2008).

2. J. C. T. Wang, Y. Sun, “Human nail and its topical treatment: brief review of current research and development of topical antifungal drug delivery for onychomycosis treatment,” Journal of Cosmetic Science 50(1), 71–76 (1999).

3. S. Murdan, “Drug delivery to the nail following topical application,” International Journal of Pharmaceutics 236(1–2), 1–26 (2002).

4. S. M. Baswan, S. K. Li, and G. B. Kasting, “Diffusion of uncharged solutes through human nail plate,” Pharmaceutical development and technology 21(2), 255–260 (2016).

5. A. K. Gupta, F. C. Simpson, “Investigational drugs for onychomycosis,” Expert Opinion on Investigational Drugs 23(1), 97–106 (2014).

6. L. W. Figueiredo Souza, S. V. T. Souza, and A. C. C. Botelho, “Randomized controlled trial comparing photodynamic therapy based on methylene blue dye and fluconazole for toenail onychomycosis,” Dermatologic Therapy 27(1), 43–47 (2014).

7. A. V. Belikov, Yu. V. Semyashkina, S. N. Smirnov, and A. D. Tavalinskaya, “Investigation of Changes in the Absorption Spectrum of Modern Chlorine-Containing Medicines for Photodynamic Therapy and Methylene Blue as a Result of Exposure to LED Emissions with a wavelength of 656±10 nm,” Optics and Spectroscopy 128(7), 980–988 (2020).

8. V. Mathur, Y. Satrawala, and M. S. Rajput, “Physical and chemical penetration enhancers in transdermal drug delivery system,” Asian Journal of Pharmaceutics 4(3), 173–183 (2010).

9. S. Mitragotri, J. Kost, “Low-frequency sonophoresis: a review,” Advanced Drug Delivery Reviews 56(5), 589–601 (2004).

10. N. A. Monteiro-Riviere, A. O. Inman, and J. E. Riviere, “Identification of the Pathway of lontophoretic Drug Delivery: Light and Ultrastructural Studies Using Mercuric Chloride in Pigs,” Pharmaceutical Research 11(2), 251–256 (1994).

11. D. I. J. Morrow, P. A. McCarron, A. D. Woolfson, and R. F. Donnelly, “Innovative strategies for enhancing topical and transdermal drug delivery,” The Open Drug Delivery Journal 1(1), 35–59 (2007).

12. M. T. Tsai, T.-Y. Tsai, S. C. Shen, C. Y. Ng, Y.-J. Lee, J.-D. Lee, and C.-H. Yang, “Evaluation of Laser-Assisted Trans-Nail Drug Delivery with Optical Coherence Tomography,” Sensors 16(12), 2111 (2016).

13. J. Neev, J. S. Nelson, M. Critelli, J. L. McCullough, E. Cheung, W. A. Carrasco, A. M. Rubenchik, L. B. Da Silva, M. D. Perry, and B. C. Stuart, “Ablation of human nail by pulsed lasers,” Lasers in Surgery and Medicine: The Official Journal of the American Society for Laser Medicine and Surgery 21(2), 186–192 (1997).

14. E. G. Bendit, “Infrared absorption spectrum of keratin. I. Spectra of α-, β-, and supercontracted keratin,” Biopolymers: Original Research on Biomolecules 4(5), 539–559 (1966).

15. X. Chen, D. Shah, G. Kositratna, D. Manstein, R. R. Anderson, and M. X. Wu, “Facilitation of transcutaneous drug delivery and vaccine immunization by a safe laser technology,” Journal of Controlled Release 159(1), 43–51 (2012).

16. A. V. Belikov, A. V. Skrypnik, A. N. Sergeev, S. N. Smirnov, and A. D. Tavalinskaya, “Er:YLF-laser microperforation of the nail plate for drug delivery,” Proceedings of SPIE 10716, 107160X (2018).

17. D. F. Lyons, V. Le, G. L. Bidwell III, W. H. Kramer, E. A. Lewis, D. Raucher, and J. J. Correia, “Structural and hydrodynamic analysis of a novel drug delivery vector: ELP [V5G3A2-150],” Biophysical Journal 104(9), 2009–2021 (2013).

18. G. Hale, M. Querry, “Optical constants of water in the 200nm to 200micron wavelength region,” Applied Optics 12(3), 555 (1973).

19. A. V. Belikov, A. D. Tavalinskaya, and S. N. Smirnov, “Investigation of the Dual-Stage Method of Active Er:YLF Laser Drug Delivery Through the Nail and Laser-Induced Transformations of the Drug Extinction Spectrum,” Lasers in Surgery and Medicine 53(8), 1122–1131 (2021).

20. A. V. Belikov, A. D. Tavalinskaya, S. N. Smirnov, and A. N. Sergeev, “Active Er-laser drug delivery using drug-impregnated gel for treatment of nail diseases,” Biomedical Optics Express 10(7), 3232–3240 (2019).

21. A. V. Belikov, S. N. Smirnov, and A. D. Tavalinskaya, “Laser delivery and spectral study of a chlorin-containing drug for the treatment of onychomycosis with sequential laser (λ = 2819 nm) and photodynamic (λ = 656 ± 10 nm) exposure,” Optics and Spectroscopy 129(6), 698–706 (2021).

22. A. S. Rzhevskiy, R. H. Guy, and Y. G. Anissimov, “Modelling drug flux through microporated skin,” Journal of Controlled Release 241, 194–199 (2016).

23. G. Yan, K. S.Warner, J. Zhang, S. Sharma, and B. K. Gale, “Evaluation needle length and density of microneedle arrays in the pretreatment of skin for transdermal drug delivery,” International Journal of Pharmaceutics 391(1–2), 7–12 (2010).

24. S. Zhang, Y. Qiu, and Y. Gao, “Enhanced delivery of hydrophilic peptides in vitro by transdermal microneedle pretreatment,” Acta Pharmaceutica Sinica B 4(1), 100–104 (2014).

25. Y. Bachhav, S. Summer, A. Heinrich, T. Bragagna, C. Böhler, and Y. N. Kali, “Effect of controlled laser microporation on drug transport kinetics into and across the skin,” Journal of Controlled Release 146(1), 31 – 36(2010).

26. A. K. Saikia, S. Aggarwal, and U. K. Mandal, “Electrically induced swelling and methylene blue release behaviour of poly (N-isopropylacrylamide-co-acrylamido-2-methylpropyl sulphonic acid) hydrogels,” Colloid and Polymer Science 293(12), 3533–3544 (2015).

27. K. F. Pavlov, P. G. Romanov, and A. A. Noskov, Examples and tasks in the course of processes and apparatuses of chemical technology, Ripol Classic, Moscow (1987) [in Russian].

28. G. V. Taranenko, “Calculation of the hydraulic resistance of failure-type trays in the mode of a moving gas-liquid layer,” ScienceRise 6(2), 23 (2016) [in Russian].

29. M. V. Masterov, M. W. Baltussen, and J. A. M. Kuipers, “Influence of the free surface on hydrodynamics in a bubble column,” Chemical Engineering Science: X 8,100077 (2020)

30. E. A. Basco, M. V. Klement’eva, A. N. Bashkatov, V. V. Tuchin, and E. A. Genina, “Diffusion of methylene blue into rat skin ex vivo,” Problemy opticheskoy fiziki i biofotoniki. SFM-2017 47 (2017) [in Russian]. ISBN 978-5-98116-224-4.

31. S. Mishra, P. Kumar, “Attenuation of methylene blue dye during riverbank filtration through sandy aquifers,” Water and Environment Journal 29(4), 507–514 (2015).

32. I. I. Jack Clifton, J. B. Leikin, “Methylene blue,” American Journal of Therapeutics 10(4), 289–291 (2003).

33. C. Komine, Y. Tsujimoto, “A small amount of singlet oxygen generated via excited methylene blue by photodynamic therapy induces the sterilization of Enterococcus faecalis,” Journal of Endodontics 39(3), 411–414 (2013).

34. L. W. F. Souza, S. V. T. Souza, and A. C. de C. Botelho, “Distal and lateral toenail onychomycosis caused by Trichophyton rubrum: treatment with photodynamic therapy based on methylene blue dye,” Anais Brasileiros de Dermatologia 89(1), 184–186 (2014).

35. W. Spencer, J. R. Sutter, “Kinetic study of the monomer-dimer equilibrium of methylene blue in aqueous solution,” Journal of Physical Chemistry 83(12), 1573–1576 (1979).

36. A. A. Selifonov, O. G. Shapoval, A. N. Mikerov, and V. V. Tuchin, “Determination of the diffusion coefficient of methylene blue solutions in dentin of a human tooth using reflectance spectroscopy and their antibacterial activity during laser exposure,” Optics and Spectroscopy 126(6), 758–768 (2019).

37. E. Alberdi, C. Gomez, “Efficiency of methylene blue-mediated photodynamic therapy vs intense pulsed light in the treatment of onychomycosis in the toenails,” Photodermatology, Photoimmunology & Photomedicine 35(2), 69–77 (2019).

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